Proteopedia

3a4o

Lyn kinase domainLyn kinase domain

Structural highlights

3a4o is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LYN_HUMAN Constitutively phosphorylated and activated in cells from a number of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) patients. Mediates phosphorylation of the BCR-ABL fusion protein. Abnormally elevated expression levels or activation of LYN signaling may play a role in survival and proliferation of some types of cancer cells.[1] [2] [3]

Function

LYN_HUMAN Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, PTK2B/PYK2, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Human Lyn tyrosine kinase is expressed in hematopoietic tissues and plays crucial roles in the signal transduction of hematopoietic immune system. Its excess activity is involved in several tumors. The crystal structure has revealed that the potent inhibitor staurosporine binds to human Lyn kinase domain at the ATP-binding site. The remarkable structural features of the staurosporine-binding region will offer valuable structural insights for the structure-based design of novel Lyn-selective inhibitors.

Structural basis for the inhibitor recognition of human Lyn kinase domain.,Miyano N, Kinoshita T, Nakai R, Kirii Y, Yokota K, Tada T Bioorg Med Chem Lett. 2009 Dec 1;19(23):6557-60. Epub 2009 Oct 13. PMID:19857964[23]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Dos Santos C, Demur C, Bardet V, Prade-Houdellier N, Payrastre B, Recher C. A critical role for Lyn in acute myeloid leukemia. Blood. 2008 Feb 15;111(4):2269-79. Epub 2007 Dec 3. PMID:18056483 doi:http://dx.doi.org/10.1182/blood-2007-04-082099
  2. ↑ Wu J, Meng F, Lu H, Kong L, Bornmann W, Peng Z, Talpaz M, Donato NJ. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood. 2008 Apr 1;111(7):3821-9. doi: 10.1182/blood-2007-08-109330. Epub 2008 Jan, 30. PMID:18235045 doi:http://dx.doi.org/10.1182/blood-2007-08-109330
  3. ↑ Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, Darnay BG, Lamothe B, Sun H, Talpaz M, Donato NJ. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008 Jul 2;100(13):926-39. doi: 10.1093/jnci/djn188. Epub, 2008 Jun 24. PMID:18577747 doi:http://dx.doi.org/10.1093/jnci/djn188
  4. ↑ Roifman CM, Ke S. CD19 is a substrate of the antigen receptor-associated protein tyrosine kinase in human B cells. Biochem Biophys Res Commun. 1993 Jul 15;194(1):222-5. PMID:7687428 doi:http://dx.doi.org/10.1006/bbrc.1993.1807
  5. ↑ Yoshida K, Kharbanda S, Kufe D. Functional interaction between SHPTP1 and the Lyn tyrosine kinase in the apoptotic response to DNA damage. J Biol Chem. 1999 Dec 3;274(49):34663-8. PMID:10574931
  6. ↑ Gaul BS, Harrison ML, Geahlen RL, Burton RA, Post CB. Substrate recognition by the Lyn protein-tyrosine kinase. NMR structure of the immunoreceptor tyrosine-based activation motif signaling region of the B cell antigen receptor. J Biol Chem. 2000 May 26;275(21):16174-82. PMID:10748115 doi:http://dx.doi.org/10.1074/jbc.M909044199
  7. ↑ O'Laughlin-Bunner B, Radosevic N, Taylor ML, Shivakrupa, DeBerry C, Metcalfe DD, Zhou M, Lowell C, Linnekin D. Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells. Blood. 2001 Jul 15;98(2):343-50. PMID:11435302
  8. ↑ Yoshida K, Weichselbaum R, Kharbanda S, Kufe D. Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage. Mol Cell Biol. 2000 Aug;20(15):5370-80. PMID:10891478
  9. ↑ Grishin AV, Azhipa O, Semenov I, Corey SJ. Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis. Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10172-7. Epub 2001 Aug 21. PMID:11517336 doi:http://dx.doi.org/10.1073/pnas.191130798
  10. ↑ Liang X, Wisniewski D, Strife A, Shivakrupa, Clarkson B, Resh MD. Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling. J Biol Chem. 2002 Apr 19;277(16):13732-8. Epub 2002 Feb 1. PMID:11825908 doi:http://dx.doi.org/10.1074/jbc.M200277200
  11. ↑ Lannutti BJ, Drachman JG. Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Blood. 2004 May 15;103(10):3736-43. Epub 2004 Jan 15. PMID:14726379 doi:http://dx.doi.org/10.1182/blood-2003-10-3566
  12. ↑ Brunati AM, Deana R, Folda A, Massimino ML, Marin O, Ledro S, Pinna LA, Donella-Deana A. Thrombin-induced tyrosine phosphorylation of HS1 in human platelets is sequentially catalyzed by Syk and Lyn tyrosine kinases and associated with the cellular migration of the protein. J Biol Chem. 2005 Jun 3;280(22):21029-35. Epub 2005 Mar 28. PMID:15795233 doi:http://dx.doi.org/10.1074/jbc.M412634200
  13. ↑ Nakata Y, Tomkowicz B, Gewirtz AM, Ptasznik A. Integrin inhibition through Lyn-dependent cross talk from CXCR4 chemokine receptors in normal human CD34+ marrow cells. Blood. 2006 Jun 1;107(11):4234-9. Epub 2006 Feb 7. PMID:16467205 doi:http://dx.doi.org/10.1182/blood-2005-08-3343
  14. ↑ Chew V, Lam KP. Leupaxin negatively regulates B cell receptor signaling. J Biol Chem. 2007 Sep 14;282(37):27181-91. Epub 2007 Jul 19. PMID:17640867 doi:http://dx.doi.org/10.1074/jbc.M704625200
  15. ↑ Zhang J, Suzuki K, Hitomi T, Siraganian RP. TOM1L1 is a Lyn substrate involved in FcepsilonRI signaling in mast cells. J Biol Chem. 2007 Dec 28;282(52):37669-77. Epub 2007 Oct 31. PMID:17977829 doi:http://dx.doi.org/10.1074/jbc.M705168200
  16. ↑ Dos Santos C, Demur C, Bardet V, Prade-Houdellier N, Payrastre B, Recher C. A critical role for Lyn in acute myeloid leukemia. Blood. 2008 Feb 15;111(4):2269-79. Epub 2007 Dec 3. PMID:18056483 doi:http://dx.doi.org/10.1182/blood-2007-04-082099
  17. ↑ Tauzin S, Ding H, Khatib K, Ahmad I, Burdevet D, van Echten-Deckert G, Lindquist JA, Schraven B, Din NU, Borisch B, Hoessli DC. Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts. Blood. 2008 Feb 15;111(4):2310-20. Epub 2007 Dec 10. PMID:18070987 doi:http://dx.doi.org/10.1182/blood-2007-05-090985
  18. ↑ Wu J, Meng F, Lu H, Kong L, Bornmann W, Peng Z, Talpaz M, Donato NJ. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood. 2008 Apr 1;111(7):3821-9. doi: 10.1182/blood-2007-08-109330. Epub 2008 Jan, 30. PMID:18235045 doi:http://dx.doi.org/10.1182/blood-2007-08-109330
  19. ↑ Malik M, Chen YY, Kienzle MF, Tomkowicz BE, Collman RG, Ptasznik A. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase. J Immunol. 2008 Oct 1;181(7):4632-7. PMID:18802065
  20. ↑ Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, Darnay BG, Lamothe B, Sun H, Talpaz M, Donato NJ. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008 Jul 2;100(13):926-39. doi: 10.1093/jnci/djn188. Epub, 2008 Jun 24. PMID:18577747 doi:http://dx.doi.org/10.1093/jnci/djn188
  21. ↑ Collins M, Tremblay M, Chapman N, Curtiss M, Rothman PB, Houtman JC. The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol. 2009 Dec 22. PMID:20028775 doi:jlb.0409227
  22. ↑ Scapini P, Pereira S, Zhang H, Lowell CA. Multiple roles of Lyn kinase in myeloid cell signaling and function. Immunol Rev. 2009 Mar;228(1):23-40. doi: 10.1111/j.1600-065X.2008.00758.x. PMID:19290919 doi:http://dx.doi.org/10.1111/j.1600-065X.2008.00758.x
  23. ↑ Miyano N, Kinoshita T, Nakai R, Kirii Y, Yokota K, Tada T. Structural basis for the inhibitor recognition of human Lyn kinase domain. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6557-60. Epub 2009 Oct 13. PMID:19857964 doi:10.1016/j.bmcl.2009.10.038

3a4o, resolution 3.00Å

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